科学家发现可预防大多数HIV毒株感染人类细胞的抗体

HIV疫苗研制的最大困难在于HIV病毒具有千变万化的变异能力。尽管如此，科学家现在已发现其万变不离其宗：HIV病毒表面的几个少数与免疫细胞结合并加以感染的区域始终不变。这样，只要新的抗体能够“抢攻”HIV与免疫细胞的结合位点，阴险狡猾的HIV就无法对免疫细胞下口，而因为无法“霸占”免疫细胞而“因粮于敌”，HIV最后只能弹尽粮绝而土崩瓦解。本文中科学家发现的两种抗体（VRC01与VRC02）就具有这样的“抢攻”能力！更令人欣慰的是，抗体本身并不与人体细胞结合，从而避免了自体免疫疾病的产生。
; C7 ]" \# J0 G3 p; l! c

8 u" M& C# k7 }- lAntibodies Found That Prevent Most HIV Strains from Infecting Human Cells


  F$ G3 e) Z- Q% T( X7 pScienceDaily (July 9, 2010) — Scientists have discovered two potent human antibodies that can stop more than 90 percent of known global HIV strains from infecting human cells in the laboratory, and have demonstrated how one of these disease-fighting proteins accomplishes this feat. According to the scientists, these antibodies could be used to design improved HIV vaccines, or could be further developed to prevent or treat HIV infection. Moreover, the method used to find these antibodies could be applied to isolate therapeutic antibodies for other infectious diseases as well.
( @" s2 C4 J  \This image shows the atomic structure of the antibody VRC01 (blue and green) binding to HIV (grey and red). The precise site of VRC01-HIV binding (red) is a subset of the area of viral attachment to the primary immune cells HIV infects. (Credit: NIAID VRC)
9 g; x# `' b6 B. e% w+ K7 f
( Z" t* X  b" m# S+ {"The discovery of these exceptionally broadly neutralizing antibodies to HIV and the structural analysis that explains how they work are exciting advances that will accelerate our efforts to find a preventive HIV vaccine for global use," says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health. "In addition, the technique the teams used to find the new antibodies represents a novel strategy that could be applied to vaccine design for many other infectious diseases."
! o( b* E* n) J) ]9 z1 u  l
6 G" n% m3 N9 }9 lLed by a team from the NIAID Vaccine Research Center (VRC), the scientists found two naturally occurring, powerful antibodies called VRC01 and VRC02 in an HIV-infected individual's blood. They found the antibodies using a novel molecular device they developed that homes in on the specific cells that make antibodies against HIV. The device is an HIV protein that the scientists modified so it would react only with antibodies specific to the site where the virus binds to cells it infects.

The scientists found that VRC01 and VRC02 neutralize more HIV strains with greater overall strength than previously known antibodies to the virus.

% S1 a  e0 O6 w8 }- ZThe researchers also determined the atomic-level structure of VRC01 when it is attaching to HIV. This has enabled the team to define how the antibody works and to precisely locate where it attaches to the virus. With this knowledge, they have begun to design components of a candidate vaccine that could teach the human immune system to make antibodies similar to VRC01 that might prevent infection by the vast majority of HIV strains worldwide.
  V6 g# K! P* O6 Y6 _NIAID scientists Peter D. Kwong, Ph.D., John R. Mascola, M.D., and Gary J. Nabel, M.D., Ph.D., led the two research teams. A pair of articles about these findings appears in the online edition of Science.

# o2 X# [8 [# _! o& O"We have used our knowledge of the structure of a virus -- in this case, the outer surface of HIV -- to refine molecular tools that pinpoint the vulnerable spot on the virus and guide us to antibodies that attach to this spot, blocking the virus from infecting cells," explains Dr. Nabel, the VRC director.
$ _" v3 U! z& ]; ^. y
3 r4 n1 h" _7 p7 w& t& w, P+ r3 qFinding individual antibodies that can neutralize HIV strains anywhere in the world has been difficult because the virus continuously changes its surface proteins to evade recognition by the immune system. As a consequence of these changes, an enormous number of HIV variants exist worldwide. Even so, scientists have identified a few areas on HIV's surface that remain nearly constant across all variants. One such area, located on the surface spikes used by HIV to attach to immune system cells and infect them, is called the CD4 binding site. VRC01 and VRC02 block HIV infection by attaching to the CD4 binding site, preventing the virus from latching onto immune cells.
"The antibodies attach to a virtually unchanging part of the virus, and this explains why they can neutralize such an extraordinary range of HIV strains," says Dr. Mascola, the deputy director of the VRC.
9 t; J7 z  `7 k6 j6 U4 Q* P# m
) z) a) L5 R+ @$ v) wWith these antibodies in hand, a team led by Dr. Kwong, chief of the structural biology section at the VRC, determined the atomic-level molecular structure of VRC01 when attached to the CD4 binding site. They then examined this structure in light of natural antibody development to ascertain the steps that would be needed to elicit a VRC01-like antibody through vaccination.
$ q4 y* D% t/ m
Antibody development begins with the mixing of genes into new combinations within the immune cells that make antibodies. Examination of the structure of VRC01 attached to HIV suggested that, from a genetic standpoint, the immune system likely could produce VRC01 precursors readily. The researchers also confirmed that VRC01 does not bind to human cells -- a characteristic that might otherwise lead to its elimination during immune development, a natural mechanism the body employs to prevent autoimmune disease.

In the final stage of antibody development, antibody-producing B cells recognize specific parts of a pathogen and then mutate, or mature, so the antibody can bind to the pathogen more firmly. VRC01 precursors do not bind tightly to HIV, but rather mature extensively into more powerfully neutralizing forms. This extensive antibody maturation presents a challenge for vaccine design. In their paper, Dr. Kwong and colleagues explore how this challenge might be addressed by designing vaccine components that could guide the immune system through this stepwise maturation process and facilitate the generation of a VRC01-like antibody from its precursors. The scientists currently are performing research to identify these components.
9 O  U: \4 j- m5 l1 R( o1 D5 M
- m/ I5 p& p: R! F0 k$ {5 `The discoveries we have made may overcome the limitations that have long stymied antibody-based HIV vaccine design," says Dr. Kwong.

6 w1 J: Q) R+ L1 c# kThe two research teams included NIAID scientists from the VRC, the Laboratory of Immunoregulation, and the Division of Clinical Research, all in Bethesda, Md.; as well as researchers from Beth Israel Deaconess Medical Center in Boston; Columbia University in New York; Harvard Medical School and Harvard School of Public Health in Boston; The Rockefeller University in New York City; and University of Washington in Seattle.

7 Y0 n2 d/ n' k5 `# w/ |http://www.sciencedaily.com/releases/2010/07/100708141531.htm

科学家发现可预防大多数HIV毒株感染人类细胞的抗体
* r* S( j$ }0 H" }
( J6 b+ p  Y2 `; j9 M《每日科学》2010年7月9日报道 —— 科学家已发现两种强力人类抗体，足以让全球已知的90%的HIV毒株停止感染实验室中的人类细胞。科学家也同时显示了这两种抗病蛋白中的其中一种完成这一壮举的具体过程（工作原理）。他们介绍说，这些抗体可用于设计改良型HIV疫苗，或继续加以开发，使之预防或治疗HIV感染。更进一步的是，发现这些抗体的方法也可用于分离有治疗作用的、对抗其它传染性疾病的抗体。
, N9 X+ ?, m/ N0 `- M/ p

' z2 K  t' c8 O! B
" h- I& z5 e8 B' A- y
. T4 H3 c, N" b6 E5 ^' @: `
3 g+ C' C! w; X! X上图显示与HIV（灰色与红色者）结合的抗体VRC01（蓝色与绿色）的原子结构。VRC01与HIV的精确结合位点（红色）是HIV所感染的原始免疫细胞的病毒附着区域的一个子集。（照片来源：NIAID VRC）

1 `0 v% a# l6 a- D1 s美国国家卫生研究院国家过敏和传染病研究所（NIAID）所长、医学博士Anthony S. Fauci说，这些具有异常广泛中和HIV能力的抗体的发现以及诠释其工作过程的结构分析代表着令人激动的长足进步，将加速可在全球范围内应用的预防性HIV疫苗的研发进程。他又指出：“另外，研究团队用于发现这种新的抗体的技术也代表着一种新的策略，可用于其它感染性疾病的疫苗设计。”

4 J3 I  h, S# Y, |, h+ ?4 s/ c+ t: H3 l由NIAID疫苗研究中心（VRC）的一个研究小组率队，科学家们在一名HIV感染者的血液中发现了两种自然出现的、强有力的抗体： VRC01与VRC02。运用自行开发的一种新颖的分子装置（这种装置可自动追踪可让抗体对抗HIV的特定细胞），他们发现了这两种抗体。该装置是科学家改造过的一种HIV蛋白，经改造的HIV蛋白只与特定抗体发生反应，这里的特定抗体是指具有“抢攻”HIV病毒与所感染的细胞相结合时的结合位点能力的抗体。
( L& I1 Q% @0 g* k( v
相对此先已知的HIV抗体而言，科学家发现VRC01与VRC02总体实力更强并能中和更多的HIV毒株。
2 I" V' v" W: [" F
6 N4 U4 r) g& _) n研究者也确定了VRC01与HIV结合时的原子水平结构。这使得该研究团队能够解释该抗体的工作原理以及准确确定抗体与HIV的结合位点。有了这一认识，他们开始设计候选疫苗的部件，使之教会人体免疫系统制造与VRC01相似的抗体从而预防世界范围内的大多数HIV毒株。
+ i1 o2 K3 A, T' O2 Y$ Y
NIAID的科学家Peter D. Kwong（哲学博士），John R. Mascola （医学博士）与Gary J. Nabel（哲学博士、医学博士）共同领导了这两个研究小组。有两篇有关这些发现的论文已刊登于网络版《Science》。

VRC负责人 Nabel 博士解释说：“我们运用了自己的病毒结构知识 （本例涉及HIV外表面结构）来改进可精确瞄准HIV‘软肋’的分子工具并指导我们成功找到了直捣这个‘软肋’的抗体；HIV的‘软肋’一旦被制，就无法感染细胞。”
; v1 d) ]4 \9 f9 `2 [+ ^
$ T0 ?! t" Z1 b$ d9 B寻找能够中和世界各地发现的各种HIV毒株的抗体一直很难，因为为了逃避免疫系统的识别，这种病毒不断改变其表面蛋白。正是由于其谲诡多变，所以世界范围内存在着数量庞大的HIV变体。尽管如此，科学家们已经确认：HIV病毒表面有少数几个区域始终如一保持不变。其中之一就是位于与免疫系统细胞结合并加以感染的HIV表面棘突上的一个区域， 该区域被称为CD4结合位点。VRC01与VRC02通过“抢攻”CD4结合位点阻断了HIV感染，从而预防了HIV病毒与免疫细胞的结合。

, ~; {5 _4 D# G' v0 r: d8 [. C“这两种抗体与HIV的结合点其实正是HIV病毒万变中始终不变的部分，这就解释了为何两种抗体能够中和范围极广的HIV毒株。”VCR副所长Mascola博士说。

手头有了这两种抗体，由VRC结构生物学部主任Kwong博士领导的一支研究小组确定了VRC01连结到CD4结合位点时的原子水平分子结构。接着他们按照天然抗体的生长过程检查了这一结构，以查明通过疫苗接种诱发VRC01样抗体所需要的步骤。
* p3 k' n+ M6 Z# r- Y/ v
在免疫细胞内，当基因混合形成新的结合物时，抗体的生长就开始了。对VRC01与HIV结合的结构的检查提示：从遗传学观点来看，免疫系统可能能够轻松生产VRC01的前身。研究者也肯定了VRC01不与人类的细胞结合，这一特点可能导致其本身在免疫发展过程的消亡 —— 这是人体为了防止自体免疫疾病而加以运用的一种自然机制。
: e- a5 J9 E* L% j& P, v
在抗体发展的最后阶段，产生抗体的B细胞识别病原体的特定部分后接着发生变异，或者说成熟了，于是抗体可与病原体更加稳固地结合。VRC01的前体与HIV的结合并不紧密，而是更成熟，成为具有强大中和能力的形式。这种抗体的全面成熟对于疫苗设计而言不啻是一个挑战。在他们的论文中，Kwong博士及其同事探索了应对挑战的方法，如设计疫苗部件，使之引导免疫系统通过该逐步成熟的过程，从而促使前体转变为VRC01样的抗体。目前科学家正在进行研究以确定这些部件。

Kwong博士说，我们的发现可能克服长期以来妨碍基于抗体的HIV疫苗设计的限制。
- k# P% o7 g; P* a$ H8 J
+ H- o5 o% ~" W* r* y$ m* Q) I两个研究小组包括来自VRC、免疫调节实验室以及临床研究分部的NIAID科学家，所有这些单位都在马里兰州的巴塞斯达；也包括来自位于波士顿的贝斯以色列迪肯尼斯医学中心、哥伦比亚大学纽约分校、哈佛医学院波士顿分院与哈佛公共卫生学院波士顿分院、洛基菲勒大学纽约分校以及华盛顿大学西雅图分校的科学家。

; t6 H1 g& u9 {/ g% k8 I4 Q' p' m& g

希望真的能起作用.